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Impaired prosaposin lysosomal trafficking in frontotemporal lobar degeneration due to progranulin mutations

Author

Listed:
  • Xiaolai Zhou

    (Weill Institute for Cell and Molecular Biology, Cornell University)

  • Lirong Sun

    (Weill Institute for Cell and Molecular Biology, Cornell University
    School of Basic Medical Sciences, Southern Medical University)

  • Oliver Bracko

    (Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University)

  • Ji Whae Choi

    (Weill Institute for Cell and Molecular Biology, Cornell University)

  • Yan Jia

    (Weill Institute for Cell and Molecular Biology, Cornell University)

  • Alissa L. Nana

    (University of California)

  • Owen Adam Brady

    (Weill Institute for Cell and Molecular Biology, Cornell University)

  • Jean C. Cruz Hernandez

    (Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University)

  • Nozomi Nishimura

    (Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University)

  • William W. Seeley

    (University of California
    University of California)

  • Fenghua Hu

    (Weill Institute for Cell and Molecular Biology, Cornell University)

Abstract

Haploinsufficiency of progranulin (PGRN) due to mutations in the granulin (GRN) gene causes frontotemporal lobar degeneration (FTLD), and complete loss of PGRN leads to a lysosomal storage disorder, neuronal ceroid lipofuscinosis (NCL). Accumulating evidence suggests that PGRN is essential for proper lysosomal function, but the precise mechanisms involved are not known. Here, we show that PGRN facilitates neuronal uptake and lysosomal delivery of prosaposin (PSAP), the precursor of saposin peptides that are essential for lysosomal glycosphingolipid degradation. We found reduced levels of PSAP in neurons both in mice deficient in PGRN and in human samples from FTLD patients due to GRN mutations. Furthermore, mice with reduced PSAP expression demonstrated FTLD-like pathology and behavioural changes. Thus, our data demonstrate a role of PGRN in PSAP lysosomal trafficking and suggest that impaired lysosomal trafficking of PSAP is an underlying disease mechanism for NCL and FTLD due to GRN mutations.

Suggested Citation

  • Xiaolai Zhou & Lirong Sun & Oliver Bracko & Ji Whae Choi & Yan Jia & Alissa L. Nana & Owen Adam Brady & Jean C. Cruz Hernandez & Nozomi Nishimura & William W. Seeley & Fenghua Hu, 2017. "Impaired prosaposin lysosomal trafficking in frontotemporal lobar degeneration due to progranulin mutations," Nature Communications, Nature, vol. 8(1), pages 1-14, August.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15277
    DOI: 10.1038/ncomms15277
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    Cited by:

    1. Yachao He & Ibrahim Kaya & Reza Shariatgorji & Johan Lundkvist & Lars U. Wahlberg & Anna Nilsson & Dejan Mamula & Jan Kehr & Justyna Zareba-Paslawska & Henrik Biverstål & Karima Chergui & Xiaoqun Zhan, 2023. "Prosaposin maintains lipid homeostasis in dopamine neurons and counteracts experimental parkinsonism in rodents," Nature Communications, Nature, vol. 14(1), pages 1-22, December.

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